M.Sc Thesis

M.Sc StudentVasiliver Gaia
SubjectIGF-I Receptor Regulates Glucose Transporter 4(GLUT4) Gene
Expression and Activity in Skeletal Growth
DepartmentDepartment of Medicine
Supervisors PROFESSOR EMERITUS Eddy Karnieli
PROF. Gila Maor


Type I diabetic (DM1) children often have a slow growth rate. We showed that the insulin sensitive glucose transporter GLUT4 is presents in skeletal growth centers. Induction of diabetes was associated with significant reduction in skeletal growth and a marked reduction in GLUT4, IGF-I receptors (IGF-IR) and insulin receptors (IR) levels. We examined the hypothesis that in skeletal growth centers IGF-IR regulates GLUT4 gene expression and function.
Tow ex-vivo models for endochondral ossification were utilized: an organ culture of the mandibular condyle and a mandibular condyle-derived chondrocytes (MCDC) culture. Cultures were treated with IGF-I, or insulin with or without neutralizing anti IGF-IR antibody.
We found that IGF-I and insulin increase the development of the condyles. However, IGF-I was more potent that insulin in stimulating glucose uptake, in intact mandibular condyles and in MCDC. Moreover, IGF-I, but not insulin, increased GLUT4 levels. Furthermore, using confocal microscopy, we showed that in transiently transfected MCDC cells with pGFP-GLUT4 plasmids, IGF-I was more potent than insulin in stimulating GLUT4 translocation to the cell membrane. This was further confirmed by immunogold staining for electron microscopy. Immuno-blocking of IGF-IR in the insulin-treated culture caused a marked reduction in GLUT4 and IGF-IR levels. Condyles obtained from IR knockout mice support the primary role of IGF-IR in this process.
Taking together, we suggest that GLUT4 is functional and important in bone metabolism and is mainly regulated by the IGF-IR. Reduction of GLUT4 secondary to reduced IGF-I levels in DM1 children may partially explain their skeletal growth retardation.